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Hereditary disorders of the glomerulus are categorized on the
basis of the demonstrated or predicted function(s) of the affected
proteins. These are somewhat arbitrary categorizations that likely
simplify the cell-cell and cell-matrix interactions that produce
disease phenotypes, as listed in Chapter 472, Table 472-1.
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Familial Hematurias:
Alport Syndrome and Thin Basement Membrane Nephropathy
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Between 30% and 50% of children with persistent
hematuria have an inherited disorder of glomerular basement membranes
(GBM). Accurate diagnosis of familial hematuria is crucial for predicting prognosis
and providing accurate reproductive counseling.
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Most children and adolescents with familial glomerular hematuria
have either Alport syndrome (AS) or thin basement membrane nephropathy
(TBMN). All patients with AS, and about 50% of those with
TBMN, have mutations in genes that code for type IV collagen proteins,
the major collagenous constituents of basement membranes. About
80% of AS patients have X-linked disease due to mutations
in COL4A5, the gene encoding the a5 chain of type IV collagen (a5[IV]).
Autosomal recessive AS accounts for about 15% of patients
and arises from mutations in both alleles of COL4A3 or COL4A4, which encode
the a3(IV) and a4(IV) chains, respectively. About 5% of
AS patients have autosomal dominant disease, due to heterozygous
COL4A3 or COL4A4 mutations. However, most people with heterozygous
mutations of COL4A3 or COL4A4 have TBMN, a nonprogressive form of familial
hematuria.
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Persistent microscopic hematuria is the hallmark of AS, occurring
in 100% of X-linked AS males, 95% of X-linked
AS females, and all patients with autosomal recessive AS. Episodic
gross hematuria is common. The onset of hematuria in X-linked AS
males occurs during infancy. Since only 10% to 15% of
children with X-linked AS have de novo mutations,
most children with X-linked AS have a parent with hematuria. However,
normal parental urinalyses do not exclude a diagnosis of X-linked
AS. Each parent of a child with autosomal recessive AS is a heterozygous carrier
of a mutation in COL4A3 or COL4A4. Since about 50% of these
carriers are symptomatic, hematuria may be found in both parents,
one parent, or neither parent.
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Microscopic hematuria is also the cardinal clinical finding in
children with TBMN, who may have episodic gross hematuria, often
in association with acute infection. TBMN is a dominant disorder,
so hematuria is frequently found in a parent.
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As TBMN is typically nonprogressive, a family history of kidney
failure in a child with hematuria suggests a diagnosis of AS. A
family history of deafness should also raise suspicion for AS. Sensorineural
deafness develops in 80% of X-linked AS males and most
patients with autosomal recessive AS. The onset of measurable hearing deficits
typically occurs in late childhood. The hearing defect is bilateral
and initially involves high-frequency wavelengths, gradually extending
into conversational speech wavelengths over time. About 40% of
X-linked AS males exhibit ocular anomalies, including maculopathy,
anterior ...